Loss of melatonin signaling increases the risk of T2DM caused by metabolic disorders

Type 2 diabetes mellitus (T2DM) poses a significant global health challenge. Genome-wide Association Studies have linked T2DM to genetic variants in the melatonin receptor 1a (MTNR1A) and 1b (MTNR1B) genes, which encode the MT1 and MT2 receptors, respectively. Our results found that the rs2119882 MT1 mutation was associated with higher blood glucose levels and increased body mass index (BMI) in humans. Metabolomic analysis showed elevated levels of palmitic acid (a saturated fatty acid) and reduced levels of oleic acid (an unsaturated fatty acid) in individuals with this mutation. In contrast, the rs10830963 MT2 mutation did not show the significant differences in blood glucose level or BMI compared to normal control individuals. Inhibition of MTNR1A and MTNR1B expression led to lower GLUT-4 mRNA and insulin receptor protein levels in human liver cells, resulting in decreased glycogen synthesis and metabolic disruptions. We used CRISPR/Cas9 to create MTNR1A and MTNR1B knockout (KO) mice, which also exhibited reduced GLUT-4 and INSR mRNA levels, decreased glucose tolerance, and increased insulin resistance. These mice also developed obesity, liver lipid deposition, increased abdominal white adipose tissue, and lower androgen levels. Metabolomic and proteomic analyses of the KO mice revealed increased triglycerides and phospholipids, and decreased unsaturated fatty acids. Proteomic studies showed reduced levels of insulin receptor tyrosine kinase, lipid droplet-associated hydrolase, and glucose-6-phosphate dehydrogenase, disrupting fatty acid metabolism and increasing liver lipid deposition. Additionally, a high-fat diet challenge in MTNR1A and MTNR1B KO male mice accelerate the INSR protein expression suppression, hepatic triglyceride accumulation, blood glucose elevation and weight gain. Finally, we generated AANAT over-expressing sheep, which showed improved glucose tolerance and higher insulin levels after glucose injection compared to WT sheep. These findings underscore the importance of melatonin and its receptors in glucose and lipid metabolism, suggesting their deficiencies may contribute to T2DM.